Non-opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury to the Young Brain (No-POPPY)

The number of newborns that develop the constellation of drug withdrawal symptoms or Neonatal Abstinence Syndrome (NAS) in the US has increased to epidemic proportions.1, 2 This is consistent with the rise in prescribed and non-prescribed opiate use as well as with the rise in heroin use.3 Aside from increased hospital length-of-stay and costs, the pharmacologic treatment of NAS with morphine, which is the standard of care during the first few weeks of life, is highly concerning as it corresponds with a timeframe of rapid postnatal brain development.4 The reported effects of morphine on the developing brain include decreased neurogenesis, synaptogenesis, and corticogenesis,5-8 decreased brain size,9 and decreased brain volumes in older children with prenatal opiate exposure.10 Although methadone is also being evaluated for the treatment of NAS, its narcotic and opioid properties pose concerns. Additionally, response to treatment is highly variable and limited pharmacogenetic and metabolic activity data, which can be used to optimize therapy in this population, pose additional challenges in using any drug to treat NAS. Collectively, these issues present a critical need to evaluate and optimize the use of a non-opioid drug for treatment of NAS. The long term goals of our research are to establish the best pharmacological treatment for NAS and determine how pharmacologic treatment of NAS affects long-term developmental outcomes. The objective of this application, in pursuit of that goal, is to evaluate the effectiveness of clonidine, an á2 adrenergic receptor agonist, as a treatment for neonates with NAS, in a randomized clinical trial. Our central hypothesis is that clonidine will effectively treat drug withdrawal manifestations in neonates. Preliminary clinical evidence supports this hypothesis. Clonidine has previously been reported by us 11 and others as a single drug therapy for NAS in small number of infants with relief of withdrawal symptoms12-15 and as an effective adjunctive treatment, when giving chloral hydrate or morphine.16-18 Mechanistically, prolonged opiate exposure results in activation of opiate receptors in the locus ceruleus, which contain clusters of noradrenergic cells.19, 20 With cessation of opiate supply, the inhibitory effect of chronic opiate on noradrenergic activity is lost, resulting in increased noradrenergic activity, which contributes to withdrawal symptoms.21 Clonidine has inhibitory effects on noradrenaline release in the locus ceruleus, decreasing noradrenergic neuronal activity and, consequently, decreasing withdrawal manifestations.22, 23 The rationale for the proposed research is that, once we understand how clonidine can be used optimally in the clinic to treat NAS, a safe medication will be available and it could potentially minimize complications associated increased length-of-stay in the hospital, healthcare costs and the deleterious opiate assaults on the developing brain that continue with postnatal opiate administration. This MPI project brings together the clinical expertise of Dr. Henrietta Bada and the pharmacology and modeling expertise of Drs. Markos Leggas and Chee Ng. This project was the result of a previous collaboration that tested this concept in a pilot study.11 To test our central hypothesis and accomplish the objective of this application we plan to pursue the following specific aims: 1. To determine whether the treatment of NAS with a non-opiate medication, clonidine, will be more effective than morphine. We hypothesize that clonidine-treated infants will have better neurobehavioral performance summary scores (self- regulation, motor/reflexes, stress/abstinence scales, etc.) using the NICU Network Neurobehavioral Scale (NNNS),24, 25 as compared to those treated with morphine. 2. To determine whether treatment of NAS with clonidine will result in better early childhood outcomes than those treated with morphine. We will test the hypothesis that compared to morphine treatment, clonidine treatment will result in higher language, cognitive, and motor functioning scores at adjusted ages of 6, 12, and 24 months as determined with Bayley Scales III,26 and lower behavior problem scores at 24 months adjusted age as determined by the Child Behavior Checklist.27 3. To build population pharmacokinetic/pharmacodynamic models and determine factors that affect exposure and response to morphine and clonidine. There is high variability in the response of infants with NAS following treatment with opioid drugs. We hypothesize that variability in response to a single drug therapy can be accounted for by pharmacogenetic factors and altered neonatal metabolic capacity. With respect to expected outcomes, this proposal will provide prospective evidence: 1) regarding the potential of clonidine treatment to result in a shorter time to control NAS, shorter total days of treatment, shorter hospital stay, and a less likely need for an adjunctive or second drug therapy; 2) regarding how opioid and non-opioid exposure affect early childhood development; 3) regarding factors that influence response to treatment. These results are expected to have an important positive impact, because they have the potential to provide fundamental information regarding the metabolic ontogeny of infants exposed to opioid drugs and, most importantly, to improve the long-term outcomes of children born to addicted mothers. Non-opiate treatment after prenatal opiate exposure to Prevent Postnatal Injury to the Young Brain (No-POPPY) REFERENCES 1. Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. 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